L-脯氨酸和噻二唑衍生物的设计、合成及其生物活性测试

发布时间：2018-10-15 12:06

【摘要】：阿尔茨海默病(Alzheimer’s Disease,AD)是一种慢性神经退行性疾病,主要特征是认知和记忆功能不断恶化,日常生活能力减退,并有各种行为障碍。目前商品化的AD治疗药物只能缓解部分AD患者的症状,且存在不同程度的副作用。因此,通过设计合成新的化学实体,寻找高效、毒副作用小的AChE抑制剂仍然是科研工作者的努力方向。本论文基于乙酰胆碱酯酶抑制剂类阿尔茨海默病治疗药物的研究现状,在系统查阅文献的基础上,分别以α-溴代苯乙酮和苯甲酸为原料合成了新的L-脯氨酸和噻二唑衍生物,并采用Ellman分光光度法测试了它们对乙酰胆碱酯酶的体外抑制活性。本文中制备的L-脯氨酸和噻二唑衍生物的化学结构均经核磁共振氢谱、高分辨质谱、红外等波谱技术进行了确证。它们对乙酰胆碱酯酶的体外抑制活性测试结果表明:L-脯氨酸衍生物具有较好的乙酰胆碱酯酶抑制活性,其中化合物8b的抑制活性最好,其IC50达到了5.45μmol·L-1,优于对照药利斯的明,同时它对丁酰胆碱酯酶几乎没有抑制活性;噻二唑衍生物也具有一定的乙酰胆碱酯酶的抑制活性,但活性较差,抑制活性最好的化合物14b的IC50值为15μmol·L-1,低于对照药利斯的明。此外,我们对生物活性较好化合物8b进行了酶抑制动力学实验,研究目标化合物与AChE的作用机制。通过绘制Line weaver-Burk图,表明化合物8b对AChE抑制方式为混合型竞争性抑制。
[Abstract]:Alzheimer's disease (Alzheimer's Disease,AD) is a chronic neurodegenerative disease characterized by deterioration of cognitive and memory functions, decline in daily life and various behavioral disorders. At present, the commercialized AD therapy can only relieve the symptoms of some AD patients, and there are some side effects. Therefore, it is still the direction of researchers to design and synthesize new chemical entities to find AChE inhibitors with high efficiency and low toxicity. Based on the research status of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease, new derivatives of L-proline and thiadiazole were synthesized from 伪 -bromoacetophenone and benzoic acid, respectively. The inhibitory activity of acetylcholinesterase on acetylcholinesterase was measured by Ellman spectrophotometry. The chemical structures of the L- proline and thiadiazole derivatives were confirmed by nuclear magnetic resonance (NMR), high resolution mass spectrometry (HRMS) and infrared spectroscopy (IR). The inhibitory activity of L- proline derivatives on acetylcholinesterase was tested in vitro. The results showed that L- proline derivatives had better inhibitory activity of acetylcholinesterase, and compound 8b had the best inhibitory activity, its IC50 reached 5.45 渭 mol L-1, which was better than that of control drug Listigmine. At the same time, it had little inhibitory activity on butyrylcholinesterase, and thiadiazole derivatives had a certain inhibitory activity of acetylcholinesterase, but the activity was poor. The IC50 value of 14b compound with the best inhibitory activity was 15 渭 mol L -1, which was lower than that of control drug Listigmine. In addition, the enzyme inhibition kinetics of 8b, a good bioactive compound, was studied to study the mechanism of the interaction between the target compound and AChE. The Line weaver-Burk diagram showed that compound 8b could inhibit AChE in a mixed competitive manner.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R91;R914
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本文编号：2272505